Diagnostic yield of whole genome sequencing after non-diagnostic exome sequencing or gene panel in developmental and epileptic encephalopathies

Abstract

OBJECTIVE: To assess the benefits and limitations of whole genome sequencing (WGS) compared to exome sequencing (ES) or multigene panel (MGP) in the molecular diagnosis of developmental and epileptic encephalopathies (DEE). METHODS: We performed WGS of 30 comprehensively phenotyped DEE patient trios that were undiagnosed after first-tier testing, including chromosomal microarray (CMA), and either research ES (n=15) or diagnostic MGP (n=15). RESULTS: 8 diagnoses were made in the 15 individuals who received prior ES (53%): 3 individuals had complex structural variants; 5 had ES-detectable variants which now had additional evidence for pathogenicity. 11 diagnoses were made in the 15 MGP-negative individuals (68%); the majority (n=10) involved genes not included in the panel, particularly in individuals with post-neonatal onset of seizures and those with more complex presentations including movement disorders, dysmorphic features and/or multi-organ involvement. 42% of diagnoses were autosomal recessive or X-chromosome linked. CONCLUSION: WGS was able to improve diagnostic yield over ES primarily through the detection of complex structural variants (n=3). The higher diagnostic yield was otherwise better attributed to the power of re-analysis rather than inherent advantages of the WGS platform. Additional research is required to assist in the assessment of pathogenicity of novel non-coding and complex structural variants and further improve diagnostic yield for patients with DEE and other neurogenetic disorders.